2. Academic Validation
  3. Discovery of phenylpyrrolidine derivatives as a novel class of retinol binding protein 4 (RBP4) reducers

Discovery of phenylpyrrolidine derivatives as a novel class of retinol binding protein 4 (RBP4) reducers

  • Bioorg Med Chem. 2022 Jan 15;54:116553. doi: 10.1016/j.bmc.2021.116553.
Shinji Nakamura 1,  Masahiro Kamaura 1,  Yuichiro Akao 1,  Natsuko Nakamura 1,  Atsushi Mizukami 1,  Akihiko Goto 1,  Naoki Furuyama 1,  Nobuo Cho 1,  Shizuo Kasai 2
Affiliations

Affiliations

  • 1 Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
  • 2 Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: [email protected].
PMID: 34953340 DOI: 10.1016/j.bmc.2021.116553
Abstract

Retinol-binding protein 4 (RBP4) is a potential drug target for metabolic and ophthalmologic diseases. A high-throughput screening of our compound library has identified a small-molecule RBP4 reducer 7a, as a hit compound. Aiming to provide a suitable tool for investigating the pharmacological effects of RBP4 reducers, we conducted a structure-activity relationship study of 7a. Exploration of the aryl head, oxazole core, and propanoic acid tail of 7a resulted in the discovery of novel, potent, and orally available phenylpyrrolidine derivatives 43b and 43c. Compound 43b had a potent and long-lasting blood RBP4-level-reducing effect when orally administered to mice at a dose as low as 0.3 mg/kg.

Keywords

Age-related macular degeneration (AMD); Diabetes; Protein–protein interaction (PPI); Retinol-binding protein 4 (RBP4); Transthyretin (TTR).

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